Haemochromatosis

Question 1

Define haemochromatosis.

Answer 1

Body iron overload resulting from excessive intestinal iron absorption which may lead to organ damage (particularly liver, joints, pancreas, pituitary and heart)

Question 2

What is the aetiology of haemochromatosis?

Answer 2

Hereditary heamochromatosis is caused by a mutation in the HFE gene on chr 6p

Most commo mutation (90%) is C282Y, less common is H63D

Question 3

What are the two suggested models for the pathogenesis of haemochromatosis?

Answer 3

Two models for pathogenesis of HH have been suggested:

Liver model

• HFE deficiency causes decreased expression of hepatic hormone “hepcidin” which causes increased duodenal iron absorption through lack of inhibitory effect of hepcidin on ferroportin (which exports iron from enterocytes into circulation)

Crypt cell model

• HFE protein interacts with transferrin receptor 1 in duodenal crypt cells, iron transported DMT1 is upregulated and more iron is absorbed

Question 4

How common is hereditary haemochromatosis?

Answer 4

• Carrier frequency is up to 1 in 10
• Prevalence of those affected ~1 in 400
• Typically aged 40-60 at presentation
• Females have later onset and less severe presentation as a result of iron loss through menstruation

Question 5

What are the clinical features of haemochromatosis?

Answer 5

May be normal, but with severe iron overload:

• Skin - pigmentation (stale-grey/bronze) resulting from increased melanin deposits, porphyria cutanea tarda
• Liver - hepatosplenomegaly
• Heart - signs of HF, arrhythmias, cardiomyopathy
• Hypogonadism - testicular atrophy, loss of hair, gynaecomastia
• Pancreas - diabetes
• Joints- arthropathy, chondrocalcinosis

Question 6

What investigations would you do for haemochromatosis?

Answer 6

1st test: transferrin saturation

Bloods:

• Iron studies- high iron, low TIBC, high ferritin and high transferrin saturation
• Gene typing for HFE

Tests for complications:

Liver: LFTs (normal or deranged); MRI (estimate degree of iron loading); liver biopsy (assess tissue damage, Perls’ stain can show iron accummulation)

Pancreas - fasting blood glucose to test for DM

Pituitary function tests - low testosteone (in men), low or inappropriately normal LH, FSH (i.e. secondary hypogonadism), 9am cortisol, TFTs, IGF-1

Heart - ECG, echocardiogram

Joint X-Ray - linear calcification (chondrocalcinosis)

Question 7

Why might ferritin not be the best investigation for haemochromatosis?

Answer 7

It is an acute phase protein so is also elevated in inflammation

Question 8

What are the risk factors for haemochromatosis?

Answer 8

• Middle age
• Male
• White
• FH
• Supplemental iron

Question 9

What is the management of haemochromatosis?

Answer 9

Stage 0 - 3yr follow up, avoid iron and vitamin C

Stage 1 - 1yr follow up, avoid iron and vitamin C

Stage 2, 3, 4 -

• Phlebotomy regimen e.g. removing 500ml blood with hct of 40% removes 200mg iron 2-weekly then weekly, monitor Hb and MCV.
• Iron chelation therapy e.g. deferasirox

Question 10

What are the stages of haemochromatosis?

Answer 10

C282Y homozygosity AND

Stage 0 - normal transferrin saturation, normal ferritin, asymptomatic

Stage 1 - increased transferrin saturation >45%, normal ferritin, asymptomatic

Stage 2 - increased transferrin saturation >45%, ferritin raised, asymptomatic

Stage 3 - increased transferrin saturation >45%, ferritin raised, early symptomatic

Stage 4 - increased transferrin saturation >45%, ferritin raised, symptomatic with organ damage

Question 11

What are the complications of haemochromatosis?

Answer 11

• Cirrhosis
• DM
• CCF
• HCC
• Hypogonadism
• Bone loss
• Infections - certain organisms, including Listeria monocytogenes, Yersinia enterocolitica, and Vibrio vulnificus

Question 12

What is the prognosis with haemochromatosis?

Answer 12

Mean survival 21yrs (small study)

Death from cancer (11%), HCC (7%), diabetes mellitus (2%), cardiomyopathy (2%), myocardial infarction (2%), and liver cirrhosis (6%)